Mlinar Boris, Mascalchi Simona, Morini Raffaella, Giachi Filippo, Corradetti Renato
Department of Preclinical and Clinical Pharmacology Mario Aiazzi-Mancini, University of Florence, Florence, Italy.
Neuropsychopharmacology. 2008 May;33(6):1464-75. doi: 10.1038/sj.npp.1301512. Epub 2007 Jul 25.
It is well documented that N-methyl-3,4-methylenedioxyamphetamine (MDMA, ecstasy) releases brain serotonin (5-HT; 5-hydroxytryptamine), noradrenaline (NE; norepinephrine), and dopamine, but the consequent effect on brain functioning remains elusive. In this study, we characterized the effects of MDMA on electrically evoked responses in the ventral CA1 region of a rat hippocampal slice preparation. Superfusion with MDMA (10 microM, 30 min) increased the population spike amplitude (PSA) by 48.9+/-31.2% and decreased population spike latency (PSL) by 103+/-139 mus (both: mean+/-SD, n=123; p<0.0001, Wilcoxon test), without affecting field excitatory postsynaptic potential (fEPSP). This effect persisted for at least 1 h after MDMA washout; we have called this EPSP-spike potentiation (ESP) by MDMA, ESP MDMA. Antagonism of GABAergic transmission did not prevent ESP MDMA, suggesting that an increase in excitability of pyramidal cells underlies this MDMA action. Block of serotonin transporter (SERT) with citalopram or 5-HT depletion with (+/-)-p-chlorophenylalanine pretreatment partially inhibited the ESP MDMA. Block of both SERT and NE transporter prevented ESP MDMA, indicating its dependence on release of both 5-HT and NE. ESP MDMA is produced by simultaneous activation of 5-HT4 and beta1 receptors, with a predominant role of 5-HT4 receptors. Block of both 5-HT4 and beta1 receptors revealed an inhibitory component of the MDMA action mediated by 5-HT1A receptor. The concentration range of MDMA which produced ESP MDMA (1-30 microM) corresponds to that commonly reached in human plasma following the ingestion of psychoactive MDMA doses, suggesting that release of both 5-HT and NE, and consequent ESP MDMA may underlie some of the psychoactive effects of MDMA in humans.
有充分的文献记载,N-甲基-3,4-亚甲基二氧苯丙胺(MDMA,摇头丸)会释放脑内的血清素(5-HT;5-羟色胺)、去甲肾上腺素(NE;去甲肾上腺素)和多巴胺,但其对脑功能的后续影响仍不清楚。在本研究中,我们表征了MDMA对大鼠海马切片制备腹侧CA1区电诱发反应的影响。用MDMA(10微摩尔,30分钟)灌流使群体峰电位幅度(PSA)增加了48.9±31.2%,群体峰电位潜伏期(PSL)缩短了103±139微秒(两者:平均值±标准差,n = 123;p < 0.0001,Wilcoxon检验),而不影响场兴奋性突触后电位(fEPSP)。这种效应在MDMA洗脱后至少持续1小时;我们将MDMA引起的这种兴奋性突触后电位-峰电位增强(ESP)称为ESP MDMA。GABA能传递的拮抗作用并不能阻止ESP MDMA,这表明锥体细胞兴奋性的增加是MDMA这种作用的基础。用西酞普兰阻断5-羟色胺转运体(SERT)或用(±)-对氯苯丙氨酸预处理使5-羟色胺耗竭可部分抑制ESP MDMA。同时阻断SERT和NE转运体可阻止ESP MDMA,表明其依赖于5-羟色胺和NE的释放。ESP MDMA是由5-HT4和β1受体的同时激活产生的,其中5-HT4受体起主要作用。同时阻断5-HT4和β1受体揭示了由5-HT1A受体介导的MDMA作用的抑制成分。产生ESP MDMA的MDMA浓度范围(1 - 30微摩尔)与摄入精神活性MDMA剂量后人体血浆中通常达到的浓度范围相对应,这表明5-羟色胺和NE的释放以及随之而来的ESP MDMA可能是MDMA对人体产生某些精神活性作用的基础。